Pharmacokinetics & Pharmacodynamics Flashcards
pharmacokinetics
how conc. of drug changes in body with time
ADME
absorption
distribution
metabolism
elimination
clinical aim of drug administration
achieve effective drug conc. (in therapeutic range) at site of action (systemic circulation) long enough to have an effect
therapeutic window vs index
window refers to population while index refers to individual patient
wider box - wider range so safe
used to use LD50 (conc that kills 50% population) divided by ED50 (effective dose)
but not ethical
bioavailability
proportion of dose of unchanged drug that reaches site of action
intravenous injection
100% bioavailability because straight to systemic circulation
need sterile equip, trained, expensive, painful
oral route (plus and minuses)
safest, most convenient, economical, always less than 100% bioavailability because destroyed by bacteria/acid/food/enzymes
absorption depends on rates of passage
some side effects and requires patient co-operation
drug absorption from GI tract to circulation
Fick’s law of passive diffusion
rate = (permeability x SA x conc diff) / thickness of membrane
what does permeability of drug depend on?
its lipid solubility
lipid soluble and small will pass better
most drugs are….
and what is better absorbed?
weak acids/bases and unionised drugs are better absorbed
other absorption methods
active transport
ion-pair absorption (+ve ion with -ve ion in gut forms neutral complex moves into blood)
pinocytosis engulfs
solvent drug (highly lipid soluble drug won’t dissolve in lumen so dissolve in solvent before drink)
sites of drug absorption
little absorption: small intestine (main site), stomach, colon
formulation
strong enough so don’t fall apart when handle but still dissolve
gut motility
gastric emptying modulated by meal size/composition, drugs, physiological state (lay/sit), migraine
orally administered drugs with potential problems
phenoxymethyl penicillin - absorbed by food so take on empty stomach
tetracyclines - absorption reduced by milk/antacids/iron
aspirin - iritate stomach
1st pass metabolism
before systemic
if drug rapidly metabolised by liver/gut then other routes?
inhalation - avoids 1st pass metabolism, straight to systemic
transdermal - across skin, hard to get across e.g. nicotine patches, ibuprofen gel
buccal+sublingual - gum+under tongue, straight to systemic
intranasal
rectal
subcutaneous - upper dermis not in muscle
intramuscular injection - large blood flow in muscles so reliable route, but can’t self administer
penicillin administration
route affect bioavailability oral - slow IV - fast IM - fast and longer duration P-IM - modified IM with much longer duration
plasma protein binding (function, free drug, what binds what, saturation of binding
drugs in plasma bound to proteins which act as buffer/carrier
only free drug is active and eliminated but free can cause toxic effects
weak acids bind plasma albumin
weak bases bind acid glycoprotein
saturation of binding is non linear relationship between dose and free conc.
a small increase in drug conc. causes large increase in free drug so toxic
tissue distribution of drug depends on….
depends on lipid solubility, plasma protein binding and molecular weight
e.g. heparin is big so doesn’t leave plasma
blood brain barrier
hard to get drugs into brain, and it pumps drugs out to have low conc.
because layer of tightly joined endothelial cells, contain P-glycoprotein (Pgp) efflux pump
lipid soluble drugs by passive diffusion
water soluble by carrier mechanisms
drug metabolism in liver by hepatocytes (what happens, and explain process)
some converted to inactive metabolites
some to active metabolites
some excreted unchanged
Phase 1 (primary metabolites): transform molecular structure of drug
Phase 2 (secondary metabolites): conjugation - attachment of endogenous substance to original drug or after phase 1, by transferases
to increase water solubility, make polar, abolish activity
then excretion
excretion
renal route via kidney
can change urinary pH to aid excretion
some drugs actively excreted like penicillin
dangerous if drug excreted unchanged
other routes of excretion
biliary into intestine - bile to gal bladder to small intestine so can absorb back into blood - enterohepatic circulation
saliva, sweat, tears, expired
breast milk - danger to baby
Vd
apparent (not real) volume of distribution
not real because some conc. of drug in plasma so small that tells you large volume than humans have
so just tells you if distributed in tissues or plasma
fraction extracted
E= (conc in - conc out)/ conc in
clearance
how well gets rid of drug
rate of elimination/conc of input
volume/time (virtual volume of blood cleared of drug per unit time)
creatine clearance rate
linear relationship between drug clearance and creatine clearance so high conc in blood means poor clearance
better than taking periodic blood samples to see drug conc change
measuring clearance
creatine clearance
blood sample
renal clearance - urine samples
normal clearance for healthy
88-128 mL/min women
97-137 mL/min male
clearance and age
decreases with age so half life of drug goes up and need to adjust dosage intervals
first order elimination kinetics (most drugs)
rate of elimination proportional to drug conc. - exponential so faster elimination more drug
kel
elimination rate constant
units time-1
proportion of drug eliminated per unit time
kel= rate of elimination/amount left
time constant
1/kel
time taken for conc. to fall 1/e (37%)
half life
time taken for drug conc to fall by half
ln2/kel
helps determine dosage interval
2 exponentials of elimination
distribution to other compartments
then slower rate elimination
both 1st order kinetics
Ka
absorption rate constant
phases of drug in body
lag time (time to get to blood)
absorption (plasma conc builds up)
elimination (eliminate/distribute)
area under curve of plasma conc (y) against time after ingestion (x)
AUC
bioavailability of drug so amount absorbed
loading dose
injection to start then orally maintain level of conc.
better than oral when need immediate effect
continuous infusion
slowly build conc. of drug over time (rapid is bad for BP) with infusion/pump
to eliminate troughs in oral graph so get smooth curve and eliminate toxicity if use loading dose
zero order kinetics
rate of elimination not proportional to drug conc but is constant
e.g. ethanol
if you start with more drug it takes longer to remove it so half life is not constant but depends on starting conc.
so constant amount eliminated
drug dosage changes
neonates have reduced body volume and higher proportion of water so reduce dose
reduce dose in elderly because higher fat than water, drug binding to plasma proteins reduced
low renal function and clearance at birth and reduced in elderly
lower metabolism
drug monitoring
monitor conc level in blood if toxic/effective
take sample at peak conc./trough conc./time above threshold value
urine sample to monitor drug
useful so don’t need blood and for drugs partially/fully eliminated in urine
but volume variable because how much drink so can’t use drug conc. but absolute amount (moles)
drug modes of action
enzyme inhibitors enzyme false substrates receptor activators receptor blockers ion channel blockers ion channel modulators neurotransmitter uptake blockers
measuring response
force of contraction, current, change in potential, amount of 2nd messenger (cAMP), loss of NT, physiological change
EC50
conc that gives 50% of max response
why is there a max response?
finite no. receptors so all occupied
or property of tissue/cell so can’t contract any more because max reached
affinity
how well drug binds receptor (not about the response)
efficacy
measure of response - how well turns receptor on to active form
low means can’t reach max response
potency
combine affinity and efficacy
k+1
k-1
association rate constant
dissociation rate constant
Kd
conc. of drug required to occupy 50% receptors
(k-1)/(k+1)
lower Kd means less drug needed so high affinity
measuring affinity
can’t measure contraction because measures efficacy as well
ligand binding assay - radio label ligand and shows when bind to receptor so radioactive shows how much bound
but must account for non-specific binding
non-specific binding
low affinity so keeps binding and doesn’t reach max - straight line
saturate with cold ligand (without label) so any radioactivity is binding to non-specific sites so subtract off total binding to get specific binding
desensitisation/tachyphylaxis
bound for long time to phosphorylated and receptor internalised so less response because less receptors or run out of mediators
tachyphylaxis is whole organ or tissue no longer responds
clinical agonists
adrenaline - increase HR and force contraction for anaphylactic shock (allergy)
salbutamol for asthma
dopamine increase HR
morphine for severe pain
partial agonsts
partial response
same affinity but not full response
conc. doesn’t matter
e.g. to reduce over-activity but not block basal activity, e.g. pain killer or treat addicts
basal activity (constitutive)
receptor’s activity in absence of ligand
partial beta agonists
beta-blockers slow heart but don’t block all beta receptors
inverse agonists
reduce basal activity of G-protein receptors (reduces response below 0)
many antagonists are inverse agonists
GABA-A receptor
main inhibitory receptor in brain
control excitation
2 binding sites for Gaba, 1 for barbiturates
B2 full agonist binds to separate site to increase opening when GABA binds (inverse agonists would bind here and decrease opening)
barbiturates
A barbiturate is a drug that acts as a central nervous system depressant and can therefore produce a wide range of effects, from mild sedation to death.
competitive antagonists
binds to receptor but doesn’t do anything but prevent agonist binding so no response
enough agonist can outcompete antagonist
don’t change max response but shift curve to right because more conc needed for 50% response
measurement of potency pA2
-ve log of molar conc. of antagonist that reduces effect of known conc of agonist to that of 1/2 conc.
(how good at blocking agonist response)
bigger value better antagonist
non-competitive antagonists
bind allosteric site or covalently to main site and stay there
diff slope gradient and not max response curve
none clinically used, but some toxins
spare receptors
sometimes don’t need to occupy all receptors to get full response (e.g. only 70% needed)
use non-competitive antagonists to get full response
if still get full response then have spare receptors
so conc. for 50% receptors is not conc. for 50% response (Kd not EC50)
